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In contrast, rat IAPP (rIAPP) is largely non\u2010amyloidogenic. Osmolytes such as glucose, glycerol, and sorbitol are known to stabilize globular protein structures; however, in the case of intrinsically disordered proteins (IDPs), they modulate amyloidogenic aggregation in a concentration\u2010dependent manner. Understanding the molecular mechanism of action of these osmolytes on IDPs remains limited. Well\u2010tempered bias exchange metadynamics (WT\u2010BEMD) simulations were used to study the conformational energy landscape of hIAPP and rIAPP in solution across varying osmolyte concentrations (125, 250, and 500\u2009mM). The addition of osmolytes resulted in subtle changes in secondary structure propensity and content in both hIAPP and rIAPP. In the case of hIAPP, a general reduction in the likelihood of \u03b1\u2010helical conformations was observed, particularly in the amyloidogenic core, suggesting a molecular mechanism for reduced aggregation in the presence of osmolytes. There was a notable lack of significant direct H\u2010bonding and hydrophobic protein\u2010osmolyte interactions, confirming the presence of a strong osmophobic effect. These findings suggest that these stabilizing osmolytes influence the conformational ensemble of hIAPP and rIAPP through exclusion from the protein surface, rather than by directly stabilizing specific conformations. The potential osmolyte\u2010mediated reduction in aggregation\u2010prone conformations in IDPs such as hIAPP may disrupt early aggregation and offer a potential strategy to mitigate hIAPP cytotoxicity.<\/jats:p>","DOI":"10.1002\/prot.70151","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T06:57:39Z","timestamp":1781506659000},"page":"1717-1737","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of Stabilizing Osmolytes on the Conformational Dynamics of Human and Rat Islet Amyloid Polypeptides"],"prefix":"10.1002","volume":"94","author":[{"given":"Kiara A.","family":"Kidman","sequence":"first","affiliation":[{"name":"Curtin Medical Research Institute, Curtin School of Diagnostic and Therapeutic Sciences Curtin University  Perth Western Australia 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